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Ref Type Journal Article
PMID (27903753)
Authors Ishikawa Y, Gamo K, Yabuki M, Takagi S, Toyoshima K, Nakayama K, Nakayama A, Morimoto M, Miyashita H, Dairiki R, Hikichi Y, Tomita N, Tomita D, Imamura S, Iwatani M, Kamada Y, Matsumoto S, Hara R, Nomura T, Tsuchida K, Nakamura K
Title A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 16 2 2017 Feb 273-284 Mol Cancer Ther
URL
Abstract Text Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here, we describe the antileukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, T-3775440 disrupted the interaction between LSD1 and growth factor-independent 1B (GFI1B), a transcription factor critical for the differentiation processes of erythroid and megakaryocytic lineage cells. Knockdown of LSD1 and GFI1B recapitulated T-3775440-induced transdifferentiation and cell growth suppression, highlighting the significance of LSD1-GFI1B axis inhibition with regard to the anti-AML effects of T-3775440. Moreover, T-3775440 exhibited significant antitumor efficacy in AEL and AMKL xenograft models. Our findings provide a rationale for evaluating LSD1 inhibitors as potential treatments and indicate a novel mechanism of action against AML, particularly AEL and AMKL. Mol Cancer Ther; 16(2); 273-84. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
T-3775440 T-3775440 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
T-3775440 KDM1A Inhibitor 15 T-3775440 is a small molecule inhibitor of KDM1A (LSD1), which may lead to antileukemic activity, including apoptotic activity and inhibition of tumor growth (PMID: 27903753, PMID: 28667074).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References